This blog is interesting...and seems to be right up Deb's alley...
March 09, 2005
Rewiring the Brain?
Just how do antidepressant drugs work? The answer you get (and the confidence with which it's delivered) will vary according to the experience of the person giving it: the more experienced and knowledgeable they are, the more tentative and uncertain the answer. I worked on central nervous system drugs for eight years, and I can confidently state that we know just slightly more than jack.
Well, the more, um, standard answer is that antidepressants act by changing the concentrations of key neurotransmitters like serotonin or noradrenaline. That's certainly what they're designed to do, by shutting off metabolic and clearance pathways and allowing serotonin, say, to build up. Underlying all this is a larger hypothesis, one so large that we usually don't even think about it: that depression is indeed a disorder of those neurotransmitters, a chemical imbalance that could in theory be righted if we just studied the relevant pathways hard enough.
There's been a feeling, though, that we've been a bit too reductionist about this. This view is well stated in a new article in Nature Reviews Neuroscience (6, 241) by Eero Castren. It's a proposal that will appeal to software engineers in particular:
"This new hypothesis, the network hypothesis, proposes that problems in activity-dependent neuronal communication might underlie depression, and that antidepressants might work by improving information processing in the affected neural networks. A key aspect of the network view is the recognition that the principal role of the nervous system is not to handle chemicals but to store and process information. . .Although chemical neurotransmitters are crucial for the transfer of information between neurons, information in the brain is not stored in a chemical form but is thought to be processed by the complex interactions of neurons in neural networks. These networks develop through interactions with the environment, and the neuronal structure of, and neurotransmission in these networks are constantly being refined. . ."
That makes the difference between the two approaches sound bigger than it really is, as Castren goes on to point out:
"It should be noted that the chemical and network hypotheses are not mutually exclusive, but are complementary. As the synthesis and release of several important signaling molecules are regulated by neuronal activity, changes in the activity of neural networks produce changes in the concentration of these signaling molecules. Therefore, although the initial effects of antidepressants are obviously chemical. . .the ensuing adaptive changes in the concentrations of those signaling molecules are tightly linked to the structure of the neural network, and might be a consequence of the altered information processing rather than its cause.
According to this view, antidepressants initiate a 'self-repair' process, whereby plasticity in neural networks and chemical neurotransmission indivisibly cooperate and gradually bring about mood elevation."
Rodent studies have shown that antidepressants stimulate the growth of new neurons, and that this correlates with their mood-elevating effects. Brain-derived neurotrophic factor (BDNF), which has long been known as a key signal for neuronal sprouting, might be the player here, as several lines of evidence have begun to implicate it in changes in mood. All this, if true, points to a combination of drug and behavior therapy as the best combination to take advantage of the brain network remodeling, and I think that this is considered the best clinical practice as well.
The author is honest about some of the evidence against the hypothesis, such as the several factors that can bring on rapid (albeit temporary) mood changes in depressed patients. Rewiring a neural network isn't going to be rapid. But these observations don't have to invalidate the hypothesis (although they could), and there are others that support it. For example, antidepressant drugs have a very slow onset of action, an effect that's been noted for decades, and many people have suspected that there must be some sort of slow reorganization going on.
So where does that leave drug discovery folks like me? We're used to going after defined targets, and "Loosening up the synapses" doesn't sound like one. Here's Castren again, and I hope that he's right:
"The hypothesis that mood represents a functional state of neural networks might sound incompatible with the efforts of rational drug development. However, the data reviewed above indicate that the antidepressant drugs that have been used successfully for several decades might function by initiating such plastic processes, apparently indirectly, by influencing monoamine metabolism. It is possible that a similar process could also be initiated through other pharmacological mechanisms, which might become the targets of new antidepressants. . ."
http://www.corante.com/pipeline/[/b]
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